Biomedical subjects
Publications and source records attributed to S Ryan.
Arthritis can affect physical, psychological, social, sexual and role function. Nurses need to enter into a therapeutic relationship with patients to address coping strategies. Care must be placed within the context of the patient's and family's life for it to be meaningful and relevant.
We have shown that osteogenic protein-1 (OP-1) (bone morphogenetic protein-7) is responsible for the induction of nephrogenic mesenchyme during embryonic kidney development. Gene knock-out studies showed that OP-1 null mutant mice die of renal failure within the first day of postnatal life. In the present study, we evaluated the effect of recombinant human OP-1 for the treatment of acute renal failure after 60 min bilateral renal artery occlusion in rats. Bioavailability studies in normal rats indicate that approximately 1.4 microg OP-1/ml is available in the circulation 1 min after intravenous administration of 250 microg/kg, which then declines steadily with a half life of 30 min. About 0.5% of the administered OP-1 dose/g tissue is targeted for OP-1 receptors in the kidney. We show that OP-1 preserves kidney function, as determined by reduced blood urea nitrogen and serum creatinine, and increased survival rate when administered 10 min before or 1 or 16 h after ischemia, and then at 24-h intervals up to 72 h after reperfusion. Histochemical and molecular analyses demonstrate that OP-1: (a) minimizes infarction and cell necrosis, and decreases the number of plugged tubules; (b) suppresses inflammation by downregulating the expression of intercellular adhesive molecule, and prevents the accumulation and activity of neutrophils; (c) maintains the expression of the vascular smooth muscle cell phenotype in pericellular capillaries; and (d) reduces programmed cell death during the recovery. Collectively, these data suggest that OP-1 prevents the loss of kidney function associated with ischemic injury and may provide a basis for the treatment of acute renal failure.
Previous studies from several laboratories have shown that the cell surface rLHR is a 85-92 kDa protein synthesized from a 68-73 kDa intracellular precursor. While all investigators agree that the cell surface rLHR binds hCG with high affinity, it is not clear if the intracellular precursor can also bind hCG. In order to directly determine if the intracellular rLHR present in cells transfected with the wild-type rLHR binds hCG with high affinity, we devised a method that selectively degrades the cell surface rLHR while preserving the intracellular rLHR. The binding of hCG to intact cells was completely lost following mild proteolysis of the cells, but binding to detergent extracts prepared from proteolyzed cells was largely preserved. Measurements of the hCG binding affinity to intact cells or to detergent extracts prepared before and after proteolysis display very similar or identical binding affinities. Since binding to nonproteolyzed intact cells, detergent extracts prepared from nonproteolyzed cells, or detergent extracts prepared from proteolyzed cells occurs only to the 85-92 kDa rLHR, the 85-92 and 68-73 kDa rLHR, and the 68-73 kDa rLHR, respectively, we conclude that the cell surface rLHR and the intracellular rLHR bind hCG with the same affinity. Quantitation of the relative abundance of the cell surface and intracellular rLHR by immunological methods indicates that transfected cells express mostly the intracellular precursor. A comparison of the binding capacity of control and proteolyzed cells with that of their detergent extracts indicates that hCG binding assays greatly underestimate the relative abundance of the intracellular rLHR.
The inter-relationship between nutrition and chronic neonatal lung disease (neonatal CLD) is complex. The most important factor in the aetiology of neonatal CLD is of course low gestational age but intra-uterine growth retardation is also a contributory factor. Both of these factors may act partly through specific nutritional deficiencies. In particular, deficiencies of nutrients which contribute to the anti-oxidant defences, have been implicated in the aetiology of neonatal CLD.
In preterm neonates a large skeletal mineral deficit builds up between birth and 40 wk postconception. During the phase of catch-up growth between 40 and 60 wk postconception there is a catch-up in peripheral skeletal mineralization, so that by the age of 1 y the skeletal mineral content is similar in preterm and term infants, despite the former being smaller, a finding that has been replicated for lumbar spinal mineralization. Later follow-up studies suggest that this catch-up persists and mineralization remains appropriate for body size. However, given the continuing abnormal growth experience of former preterm individuals, it would still be important to examine their bone mineralization in early adulthood. A number of interventions can improve perinatal bone mineralization, but few studies examine their long-term effectiveness. One such study has suggested that a relatively poor mineral diet in this period is, counterintuitively, associated with a later advantage in skeletal mineralization. If this finding is repeatable, then it could result in a major change in nutrition strategy in the neonatal period.
OBJECTIVES: To evaluate the toxicity and clinical efficacy of liposomal encapsulated doxorubicin (DOX-SL) in the treatment of HIV-related Kaposi's sarcoma (KS). METHODS: DOX-SL 20-40mg/m2 was administered by intravenous infusion over 30-60 minutes every two weeks. Toxicity was assessed in all patients and response assessed in patients who completed two or more cycles of therapy. RESULTS: Twenty-five patients with KS were enrolled. Nine had received previous KS chemotherapy but only one prior anthracycline therapy. Eighteen patients had CD4 counts < 50/mm3. Eight had pulmonary and/or visceral KS. A total of 191 cycles were given, median 6, range 1-33. Twenty patients completed two or more cycles and were considered evaluable for efficacy. A defined response occurred in 11 patients, nine achieving a partial response and two a complete response. The median duration of response was 120 days and the median time to disease progression was 187 days. Acute toxicity was minimal, except in one patient who had generalised erythema, hypotension and diaphoresis within ten minutes of starting DOX-SL infusion. Grade 3 or 4 neutropenia occurred in 13.6 and 3.7% of cycles respectively. Neutropenic sepsis secondary to drug therapy was not reported. Alopecia and gastrointestinal symptoms were mild and infrequent. No cardiac toxicity was seen. Nine/25 patients developed HIV-associated illnesses while on study (three Pneumocystis carinii pneumonia, two systemic Cytomegalovirus infection, three cryptosporidiosis, one Mycobacterium avium intracellulare--(MAC) infection). Median survival in the evaluable patients was 219 days. CONCLUSIONS: DOX-SL is an effective and well tolerated palliative therapy in AIDS-related KS.
Osteogenic protein-1 (OP-1) is a member of the transforming growth factor beta superfamily and is a potent modulator of osteogenesis and bone cell differentiation. This preclinical study in dogs sought to assess the effects of OP-1 on periodontal wound healing in surgically created critical size Class III furcation defects. Eighteen male beagle dogs were subjected to the creation of bilateral mandibular 5 mm osseous defects. A split-mouth design was utilized which randomly assigned opposing quadrants to control therapy (surgery alone or collagen vehicle) or 1 of 3 ascending concentrations of OP-1 in a collagen vehicle (0.75 mg OP-1/g collagen, 2.5 mg/g, or 7.5 mg/g). Thus, 9 quadrants per test group received OP-1, 9 quadrants per control group received surgery alone, and 9 quadrants received collagen vehicle alone. Test articles were delivered by a surgeon masked to the treatment, and fluorogenic bone labels were injected at specified intervals post-treatment. Eight weeks after defect creation and OP-1 delivery, tissue blocks of the mandibulae were taken for masked histomorphometric analysis to assess parameters of periodontal regeneration (e.g., bone height, bone area, new attachment formation, and percent of defect filled with new bone). Histomorphometry revealed limited evidence of osteogenesis, cementogenesis, and new attachment formation in either vehicle or surgery-alone sites. In contrast, sites treated with all 3 concentrations of OP-1 showed pronounced stimulation of osteogenesis, regenerative cementum, and new attachment formation. Lesions treated with 7.5 mg/g of OP-1 in collagen regenerated 3.9+/-1.7 mm and 6.1+/-3.4 mm2 (mean +/-S.D.) of linear bone height and bone area, respectively. Furthermore, these differences were statistically different from both control therapies for all wound healing parameters (P < 0.0001). No significant increase in tooth root ankylosis was found among the treatment groups when compared to the surgery-alone group. We conclude that OP-1 offers promise as an attractive candidate for treating severe periodontal lesions.
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The Uniform Needs Assessment Instrument (UNAI) was developed to systematically assess the continuing care needs of high-risk older adults in response to the 1986 Omnibus Budget Reconciliation Act. Based on previous studies, a revised UNAI was tested with 103 hospitalized older adults, comparing usual discharge planning with the UNAI. High interrater reliability was obtained. The UNAI had high (> or = 85%) sensitivity and specificity when comparing needs identification on the UNAI with subjects' reported needs at 10 to 14 days after discharge. Overall, the UNAI was more effective (sensitive and specific).
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Monoclonal antibody HTP IV-#1 specifically recognizes a complexation-dependent neoepitope on bone acidic glycoprotein-75 (BAG-75) and a Mr = 50 kDa fragment. Complexes of BAG-75 exist in situ, as shown by immunofluorescent staining of the primary spongiosa of rat tibial metaphysis and osteosarcoma cell micromass cultures with monoclonal antibody HTP IV-#1. Incorporation of BAG-75 into complexes by newborn growth plate and calvarial tissues was confirmed with a second, anti-BAG-75 peptide antibody (#503). Newly synthesized BAG-75 immunoprecipitated from mineralizing explant cultures of bone was present entirely in large macromolecular complexes, while immunoprecipitates from monolayer cultures of osteoblastic cells were previously shown to contain only monomeric Mr = 75 kDa BAG-75 and a 50 kDa fragment. Purified BAG-75 self-associated in vitro to form large spherical aggregate structures composed of a meshwork of 10 nm diameter fibrils. These structures have the capacity to sequester large amounts of phosphate ions as evidenced by X-ray microanalysis and by the fact that purified BAG-75 preparations, even after extensive dialysis against water, retained phosphate ions in concentrations more than 1,000-fold higher than can be accounted for by exchange calculations or by electrostatic binding. The ultrastructural distribution of immunogold-labeled BAG-75 in the primary spongiosa underlying the rat growth plate is distinct from that for other acidic phosphoproteins, osteopontin and bone sialoprotein. We conclude that BAG-75 self-associates in vitro and in vivo into microfibrillar complexes which are specifically recognized by monoclonal antibody HTP IV-#1. This propensity to self-associate into macromolecular complexes is not shared with acidic phosphoproteins osteopontin and bone sialoprotein. We hypothesize that an extracellular electronegative network of macromolecular BAG-75 complexes could serve an organizational role in forming bone or as a barrier restricting local diffusion of phosphate ions.
For rheumatology nurses, role extension means taking responsibility for monitoring the drugs used in the treatment of inflammatory arthritis. This article describes how nurseled monitoring works in one clinic, and how it may offer a more holistic type of care.
Activated protein C resistance caused by an Arg506Gln mutation in the factor V gene (factor V Leiden mutation) is the most common cause of familial thrombosis. This mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is not a significant risk factor for ischemic stroke in adults. We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden mutation. One infant had multiple thrombi in the fetal placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of in utero cerebrovascular disease and hemiplegic cerebral palsy.
Six major venom fractions were obtained when crude Aipysurus laevis (Olive sea snake) venom was fractionated by standard HPLC techniques. Subcutaneous doses of between 9.5-20.3 micrograms venom/kg body weight were injected into male Quackenbush mice, showing that all six fractions of A. laevis venom are nephrotoxic, producing renal lesions within 24 hrs and lasting for up to three months. It is postulated that each fraction contains a nephrotoxic component, suggesting a core or common biochemical structure, the nature of which is to yet to be determined; and those from different fractions may act synergistically. The resulting renal lesions are no different from those seen in our previous whole venom study, but the severity is less and shorter in duration. A significant difference is that after fraction injection, the kidneys returned to normality after two months, with minor segmental glomerulosclerosis being the only remaining stigma of the previous damage. This is contrary to the whole venom-induced tubulo-interstitial nephritis with cystic changes seen after three months of envenomation. All fractions also increase the granularity of the juxtaglomerular cells, for reasons unknown.
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Conventional myosin II plays a fundamental role in the process of cytokinesis where, in the form of bipolar thick filaments, it is thought to be the molecular motor that generates the force necessary to divide the cell. In Dictyostelium, the formation of thick filaments is regulated by the phosphorylation of three threonine residues in the tail region of the myosin heavy chain. We report here on the effects of this regulation on the localization of myosin in live cells undergoing cytokinesis. We imaged fusion proteins of the green-fluorescent protein with wild-type myosin and with myosins where the three critical threonines had been changed to either alanine or aspartic acid. We provide evidence that thick filament formation is required for the accumulation of myosin in the cleavage furrow and that if thick filaments are overproduced, this accumulation is markedly enhanced. This suggests that myosin localization in dividing cells is regulated by myosin heavy chain phosphorylation.
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